CN101979382A

CN101979382A - Aminoindazole derivatives and use thereof as kinase inhibitors

Info

Publication number: CN101979382A
Application number: CN2010105043043A
Authority: CN
Inventors: D·莱叙斯; G·迪特吕克-罗塞; F·阿莱; D·巴班; T·鲁尼; G·蒂拉博斯奇
Original assignee: Aventis Pharma SA
Current assignee: Aventis Pharma SA
Priority date: 2002-12-12
Filing date: 2003-09-03
Publication date: 2011-02-23
Also published as: JP2006516266A; FR2848554A1; CN1713909A; ZA200504681B; JP4764168B2; PE20091629A1; AR041132A1; PE20040996A1; ATE520399T1; TWI345561B; MY138085A; RS20050421A; MEP25308A; TW200422293A

Abstract

The invention relates to novel aminoindazole derivatives having general formula (I) and to the use thereof for the treatment of diseases that can result from abnormal kinase activity.

Description

Aminoindazole derivatives and as the purposes of kinase inhibitor

The application is the Chinese invention patent application (applying date: on September 3rd, 2003; Application number: 038256169 (international application no: PCT/FR2003/002634); Denomination of invention: Aminoindazole derivatives and as the purposes of kinase inhibitor) divide an application.

The present invention relates to formula (I) derivative:

Or its pharmacologically acceptable salt is as the purposes of kinase inhibitor.

Theme of the present invention is to utilize formula (I) Aminoindazole derivatives and pharmacologically acceptable salt thereof to prepare the pharmaceutical composition that expection is used to prevent and treats the disease that may be caused by abnormal kinase, for example, described disease relates to neurodegenerative disease, Alzheimer, Parkinson's disease, os frontoparietale (frontoparietal) dementia, corticobasal degeneration, Pick's disease, apoplexy, cranium and trauma of spinal cord and peripheral neuropathy, obesity, metabolic disease, type ii diabetes, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, X syndrome, immune deficiency and cancer, this pharmaceutical composition comprise new Aminoindazole derivatives and pharmacologically acceptable salt and new Aminoindazole derivatives and pharmacologically acceptable salt thereof.

Described among the patent application WO 02/074388 and be (a) type Aminoindazole derivatives of potassium channel activator:

Wherein G is

Z is NX0, S or O;

E is N or CX1;

Y is halogen, X2 or OX2;

X0, X1 and X2 are the alkyl of halogen, alkyl or replacement;

A, B and D be hydrogen, halogen, replacement or unsubstituted alkyl, C (O) _pR13, C (O) NR13R14, SO ₂NR13, R14, S (O) _pR15, OR15 or NR13R14;

P is the 0-2 integer;

R13 and R14 are hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocycle, replacement or unsubstituted assorted alkyl, replacement or unsubstituted heteroaryl-assorted alkyl or replace or unsubstituted aryl-assorted alkyl;

R15 for that replace or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocycle, replacement or unsubstituted assorted alkyl, replacement or unsubstituted heteroaryl-assorted alkyl or replace or unsubstituted aryl-assorted alkyl.

The present invention relates to formula (I) derivative as giving a definition, wherein:

R3 be (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, with (1-10C) Cycloalkylfused aryl or heteroaryl, heterocycle, Heterocyclylalkyl, cycloalkyl, adamantyl, multi-ring alkyl, alkenyl, alkynyl group, CONR1R2, CSNR1R2, COOR1, SO ₂R1, C (=NH) R1 or C (=NH) NR1 base; These groups are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, CN, NO ₂, NH ₂, OH, OR1, COOH, C (O) OR1 ,-O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S (O) R1, SO ₂R1, NHSO ₂R1, SO ₂NR1R2, C (S) NR1R2, NHC (S) R1 ,-O-SO ₂R1 ,-SO ₂-O-R1, aryl, heteroaryl, heterocycle, formyl radical, trifluoromethyl, trifluoromethylthio, trifluoromethoxy or (1-6C) alkyl;

R5, R6 and R7 are independently from each other following groups: halogen, CN, NO2, NH ₂, OH, COOH, C (O) OR8 ,-O-C (O) R8, NR8R9, NHC (O) R8, C (O) NR8R9, NHC (S) R8, C (S) NR8R9, SR8, S (O) R8, SO ₂R8, NHSO ₂R8, SO ₂NR8R9 ,-O-SO ₂R8 ,-SO ₂-O-R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxyl group, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, heterocycle, cycloalkyl, alkenyl, alkynyl group, adamantyl or multi-ring alkyl; These groups are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, CN, NO ₂, NH ₂, OH, OR10, COOH, C (O) OR10 ,-O-C (O) R10, NR10R11, NHC (O) R10, C (O) NR10R11, NHC (S) R10, C (S) NR10R11, SR10, S (O) R10, SO ₂R10, NHSO ₂R10, SO ₂NR10R11 ,-O-SO ₂R10 ,-SO ₂-O-R10, aryl, heteroaryl, formyl radical, trifluoromethyl, trifluoromethoxy or (1-6C) alkyl;

R1, R2, R8, R9, R10 and R11 are hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl group, heteroaryl independently of one another, they itself are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, (1-6C) alkyl, (1-6C) alkoxyl group, CN, NO ₂, NH ₂, OH, COOH, COO alkyl, CONH ₂, formyl radical, trifluoromethyl, trifluoromethoxy;

R1 and R2 or R8 and R9 or R10 and R11 can form 5-or the 6-unit ring that contains or do not contain heteroatoms such as O, S or N;

And when R3 was 6-membered nitrogen-containing heteroaryl base or thiazolyl or imidazolyl Huo oxazolyl, at least one was an aryl unsubstituted or that replaced by one or more substituting groups in R5 and the R6 base, and described substituting group is selected from halogen, CN, NO ₂, NH ₂, OH, OR10, COOH, C (O) OR10 ,-O-C (O) R10, NR10R11, NHC (O) R10, C (O) NR10R11, NHC (S) R10, C (S) NR10R11, SR10, S (O) R10, SO ₂R10, NHSO ₂R10, SO ₂NR10R11 ,-O-SO ₂R10 ,-SO ₂-O-R10, aryl, heteroaryl, formyl radical, trifluoromethyl, trifluoromethoxy or (1-6C) alkyl;

Its racemic modification, enantiomer or diastereomer and composition thereof, its tautomer and pharmacologically acceptable salt thereof.

Especially, the present invention relates to formula (I) derivative as giving a definition, wherein:

R5 and R6 are independently from each other following groups: halogen, CN, NO ₂, NH ₂, OH, COOH, C (O) OR8 ,-O-C (O) R8, NR8R9, NHC (O) R8, C (O) NR8R9, NHC (S) R8, C (S) NR8R9, SR8, S (O) R8, SO ₂R8, NHSO ₂R8, SO ₂NR8R9 ,-O-SO ₂R8 ,-SO ₂-O-R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxyl group, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, heterocycle, cycloalkyl, alkenyl, alkynyl group, adamantyl, multi-ring alkyl; These groups are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, CN, NO ₂, NH ₂, OH, OR10, COOH, C (O) OR10 ,-O-C (O) R10, NR10R11, NHC (O) R10, C (O) NR10R11, NHC (S) R10, C (S) NR10R11, SR10, S (O) R10, SO ₂R10, NHSO ₂R10, SO ₂NR10R11 ,-O-SO ₂R10 ,-SO ₂-O-R10, aryl, heteroaryl, formyl radical, trifluoromethyl, trifluoromethoxy or (1-6C) alkyl;

R7 is halogen, methyl, cyclopropyl, CN, OH, methoxyl group, trifluoromethyl, vinyl, ethynyl, trifluoromethoxy, NO ₂, NH ₂Or NMe ₂

R1, R2, R8, R9, R10 and R11 are hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl group or heteroaryl independently of one another, they itself are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, (1-6C) alkyl, (1-6C) alkoxyl group, CN, NO ₂, NH ₂, OH, COOH, COO alkyl, CONH ₂, formyl radical, trifluoromethyl or trifluoromethoxy;

And when R3 was 6-membered nitrogen-containing heteroaryl base or thiazolyl, imidazolyl Huo oxazolyl, at least one was an aryl unsubstituted or that replaced by one or more substituting groups in R5 and the R6 base, and described substituting group is selected from halogen, CN, NO ₂, NH ₂, OH, OR10, COOH, C (O) OR10 ,-O-C (O) R10, NR10R11, NHC (O) R10, C (O) NR10R11, NHC (S) R10, C (S) NR10R11, SR10, S (O) R10, SO ₂R10, NHSO ₂R10, SO ₂NR10R11 ,-O-SO ₂R10 ,-SO ₂-O-R10, aryl, heteroaryl, formyl radical, trifluoromethyl, trifluoromethoxy and (1-6C) alkyl;

The present invention preferably relates to as the formula of giving a definition (I) derivative, wherein:

R3 be (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, with (1-10C) Cycloalkylfused aryl or heteroaryl, heterocycle, Heterocyclylalkyl, cycloalkyl, adamantyl, multi-ring alkyl, alkenyl, alkynyl group, CONR1R2, CSNR1R2, COOR1, SO ₂R1 or C (=NH) NR1 base; These groups are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, CN, NO ₂, NH ₂, OH, OR1, COOH, C (O) OR1 ,-O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S (O) R1, SO ₂R1, NHSO ₂R1, SO ₂NR1R2, C (S) NR1R2, NHC (S) R1 ,-O-SO ₂R1 ,-SO ₂-O-R1, aryl, heteroaryl, formyl radical, oxo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy or (1-6C) alkyl;

R5 is an aryl;

R6 and R7 are halogen, methyl, cyclopropyl, CN, OH, methoxyl group, trifluoromethyl, vinyl, ethynyl, trifluoromethoxy, NO independently of one another ₂, NH ₂Or NMe ₂

R1 and R2 are hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl group or heteroaryl independently of one another, they itself are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, (1-6C) alkyl, (1-6C) alkoxyl group, CN, NO ₂, NH ₂, OH, COOH, COO alkyl, CONH ₂, formyl radical, oxo, trifluoromethyl or trifluoromethoxy;

R1 and R2 can form 5-or the 6-unit ring that contains or do not contain heteroatoms such as O, S or N;

R5 is an aryl;

R6 is halogen, methyl, cyclopropyl, CN, OH, methoxyl group, trifluoromethyl, vinyl, ethynyl, trifluoromethoxy, NO ₂, NH ₂Or NMe ₂

R7 is a halogen;

R1 and R2 can form 5-or the 6-unit ring that does not contain or contain heteroatoms such as O, S or N;

In contextual definition, (1-6C) alkyl comprises 1-6 straight or branched carbon atom; Alkenyl comprises 2-6 straight or branched carbon atom and 1-3 conjugated or unconjugated pair of key; Alkynyl group comprises 2-6 straight or branched carbon atom and 1-3 conjugated or unconjugated triple bond; Aryl is selected from phenyl, naphthyl or indenyl; Heteroaryl comprises 3-10 ring members, do not comprise or comprise one or more heteroatomss that are selected from oxygen, sulphur and nitrogen, particularly, thiazolyl, thienyl, pyrryl, pyridyl, furyl, imidazolyl, oxazolyl, pyrazinyl, tetrazyl, oxadiazole base, thiadiazolyl group, Yi oxadiazole base, different thiadiazolyl group, isothiazolyl, isoxazolyl, triazolyl, pyrazolyl or indyl; Halogen radical is chlorine, iodine, fluorine or bromine; Multi-ring alkyl is selected from adamantyl, quinuclidinyl, Camphanyl, norcamphane base, borneol thiazolinyl or norbornene; The heteroaryl Cycloalkylfused with (1-10C) is selected from indanyl, isochroman base, chromanyl, 1,2,3,4-tetrahydro isoquinolyl or 1,2,3,4-tetrahydric quinoline group; Heterocyclic radical comprises 1-2 and is selected from the heteroatoms of oxygen, sulphur or nitrogen and is expressed as piperidyl, morpholinyl, pyrrolidyl, imidazolidyl, pyrazolidyl, isothiazole alkyl, thiazolidyl, isoxazole alkyl, oxazolidinyl, piperazinyl, azetidinyl, 2-piperidone, 3-piperidone, 4-piperidone, 2-Pyrrolidone or 3-pyrrolidone especially.

Formula (I) compound has one or more unsymmetrical carbons, therefore may exist with isomers, racemic modification, enantiomer and diastereomeric form; The latter comprises that its mixture also constitutes part of the present invention.

The formula of using among the present invention (I) compound can be mentioned following compounds:

N-(two the ring [2.2.1] heptan-5-alkene-2-ylmethyl)-6-chloro-7-fluoro-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3, the 3-dimethylbutyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3-phenyl propyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(cyclopropyl methyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(cyclopentyl-methyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[3-(methylthio group) propyl group]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(phenylethyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(cyclohexyl methyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-propyl group-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(2,2,3,3,4,4,4-seven fluorine butyl)-5-phenyl-1H-indazole-3-amine hydrate;

6-chloro-7-fluoro-N-(4,4,4-trifluoro butyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(4-p-methoxy-phenyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(phenyl methyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(4-cyano-phenyl) methyl]-5-phenyl-1H-indazole-3-amine;

The N-[(4-chloro-phenyl-) methyl]-6-chloro-7-fluoro-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(3-p-methoxy-phenyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[[4-(trifluoromethoxy) phenyl] methyl]-5-phenyl-1H-indazole-3-amine;

N-[4-[[[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl] amino] methyl] phenyl] ethanamide;

6-chloro-7-fluoro-N-[(3, the 5-dichlorophenyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[[4-(trifluoromethyl) phenyl] methyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(4-fluorophenyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[3-(4-methylphenoxy) phenyl methyl]-5-phenyl-1H-indazole-3-amine;

N-(2,2,3,3,4,4,4-seven fluorine butyl)-6-chloro-7-fluoro-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[[3, two (trifluoromethyl) phenyl of 5-] methyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[[3-(trifluoromethyl) phenyl] methyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(6-methoxyl group-2-naphthyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(pentafluorophenyl group) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[[4-(methylthio group) phenyl] methyl]-5-phenyl-1H-indazole-3-amine;

N-[(4-chloro-3-fluorophenyl) methyl]-6-chloro-7-fluoro-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(3,3, the 3-trifluoro propyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(3-thienyl methyl)-1H-indazole-3-amine;

N-(1,1 '-xenyl-4-ylmethyl)-6-chloro-7-fluoro-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[[4-(dimethylamino) phenyl] methyl]-5-phenyl-1H-indazole-3-amine;

N-(2,2 '-bithiophene-5-ylmethyl)-6-chloro-7-fluoro-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[[1-(phenyl methyl)-1H-imidazoles-2-yl] methyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[[1-methyl isophthalic acid H-imidazoles-2-yl] methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(1-Methyl-1H-indole-3-yl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(5-methyl-2-furyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(1H-pyrroles-2-ylmethyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[(1H-imidazoles-2-yl) methyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[(1H-imidazol-4 yl) methyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(1H-pyrazole-3-yl methyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[[2-methyl isophthalic acid H-imidazol-4 yl] methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(3,5-dimethyl-1-phenyl-1H-pyrazoles-4-yl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[[2-phenyl-1H-imidazol-4 yl] methyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[[5-(4-chloro-phenyl-)-2-furyl] methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[(1-methyl isophthalic acid H-pyrroles-2-yl) methyl]-1H-indazole-3-amine;

4-[5-[[[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl] amino] methyl]-the 2-furyl]-benzsulfamide;

6-chloro-7-fluoro-5-phenyl-N-(3-thienyl methyl)-1H-indazole-3-amine;

2-[[[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl] amino] methyl]-5-(methylthio group)-1H-imidazoles-4-ethyl formate;

6-chloro-7-fluoro-5-phenyl-N-[[5-[4-(trifluoromethyl) phenyl]-the 2-furyl] methyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[2-(piperidino) ethyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[2-(4-morpholinyl) ethyl]-5-phenyl-1H-indazole-3-amine;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(3, the 5-dichlorophenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(2-propenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(phenyl methyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-Phenoxyphenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-p-methoxy-phenyl) methyl] urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-[4-(trifluoromethyl) phenyl] urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-p-methoxy-phenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-cyclohexyl urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-propyl group urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-chloro-phenyl-) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-fluorophenyl) urea;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-N '-(three ring [3.3.1.1 ^3,7] last of the ten Heavenly stems)-1-base urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-aminomethyl phenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-methyl-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-cyano group-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-cyclopropyl-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-hydroxyl-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-methoxyl group-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-trifluoromethyl-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-trifluoromethoxy-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-nitro-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-amino-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-dimethylamino-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-ethynyl-5-phenyl-1H-indazole-3-yl) urea;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-4-methyl-benzsulfamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl] Toluidrin;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-2-third sulphonamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-2,2,2-trifluoro ethyl sulfonamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-the 2-thiophenesulfonamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl] benzsulfamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-4-(trifluoromethyl) benzsulfamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-5-(3-isoxazolyl)-2-thiophenesulfonamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-4-fluorobenzene sulphonamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-the 4-methoxybenzenesulphoismide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl] the benzene Toluidrin;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-1-methyl isophthalic acid H-imidazoles-4-sulphonamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-4-(1, the 1-dimethyl ethyl) benzsulfamide;

N-[4-[[(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl) amino] alkylsulfonyl] phenyl] ethanamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-4-methylbenzene Toluidrin;

6-chloro-7-fluoro-N-(pentafluorophenyl group)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3, the 4-difluorophenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(2,3,5,6-tetrafluoro phenyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(2,4, the 6-trifluorophenyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(4-fluorophenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[3-(trifluoromethyl) phenyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[4-(trifluoromethyl) phenyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[3-fluoro-5-(trifluoromethyl) phenyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(4-nitrophenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3-nitrophenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3-p-methoxy-phenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(4-p-methoxy-phenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N, 5-phenylbenzene-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(1-pyridyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(2-pyridyl)-5-phenyl-1H-indazole-3-amine;

N-butyl-6-chloro-7-fluoro-5-phenyl-1H-indazole-3-amine;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-phenylurea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-3-methoxybenzenesulphoismide;

Its isomer, its mixture, its racemic modification, enantiomer, diastereomer or tautomer and pharmacologically acceptable salt thereof.

And following compounds especially:

Piperidines-1-formic acid (6,7-two fluoro-5-phenyl-1H-indazole-3-yl) acid amides;

Tetramethyleneimine-1-formic acid (6,7-two fluoro-5-phenyl-1H-indazole-3-yl) acid amides;

1-(6,7-two fluoro-5-phenyl-1H-indazole-3-yl)-3-[3-(4-methylpiperazine-1-yl) propyl group] urea;

N-(6,7-two fluoro-5-phenyl-1H-indazole-3-yl)-N '-phenylurea;

Its tautomer and pharmacologically acceptable salt thereof.

The present invention also relates to comprise the pharmaceutical composition of formula (I) derivative as active effective constituent, wherein:

R3 be (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, with (1-10C) Cycloalkylfused aryl or heteroaryl, heterocycle, Heterocyclylalkyl, cycloalkyl, adamantyl, multi-ring alkyl, alkenyl, alkynyl group, CONR1R2, CSNR1R2, COOR1, SO ₂R1, C (=NH) R1 or C (=NH) NR1 base; These groups are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from CN, NO ₂, NH ₂, OH, OR1, COOH, C (O) OR1 ,-O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S (O) R1, SO ₂R1, NHSO ₂R1, SO ₂NR1R2, C (S) NR1R2, NHC (S) R1 ,-O-SO ₂R1 ,-SO ₂-O-R1, aryl, heteroaryl, heterocycle, formyl radical, trifluoromethyl, trifluoromethylthio, trifluoromethoxy or (1-6C) alkyl;

R5, R6 and R7 are independently from each other following groups: halogen, CN, NO ₂, NH ₂, OH, COOH, C (O) OR8 ,-O-C (O) R8, NR8R9, NHC (O) R8, C (O) NR8R9, NHC (S) R8, C (S) NR8R9, SR8, S (O) R8, SO ₂R8, NHSO ₂R8, SO ₂NR8R9 ,-O-SO ₂R8 ,-SO ₂-O-R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxyl group, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, heterocycle, cycloalkyl, alkenyl, alkynyl group, adamantyl or multi-ring alkyl; These groups are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, CN, NO ₂, NH ₂, OH, OR10, COOH, C (O) OR10 ,-O-C (O) R10, NR10R11, NHC (O) R10, C (O) NR10R11, NHC (S) R10, C (S) NR10R11, SR10, S (O) R10, SO ₂R10, NHSO ₂R10, SO ₂NR10R11 ,-O-SO ₂R10 ,-SO ₂-O-R10, aryl, heteroaryl, formyl radical, trifluoromethyl, trifluoromethoxy or (1-6C) alkyl;

The invention particularly relates to and comprise the pharmaceutical composition of formula (I) derivative as active effective constituent, wherein:

And when R3 was 6-membered nitrogen-containing heteroaryl base or thiazolyl, imidazolyl Huo oxazolyl, at least one was unsubstituted or by the aryl of one or more replacements and replacement, described substituting group is selected from halogen, CN, NO in R5 and the R6 base ₂, NH ₂, OH, OR10, COOH, C (O) OR10 ,-O-C (O) R10, NR10R11, NHC (O) R10, C (O) NR10R11, NHC (S) R10, C (S) NR10R11, SR10, S (O) R10, SO ₂R10, NHSO ₂R10, SO ₂NR10R11 ,-O-SO ₂R10 ,-SO ₂-O-R10, aryl, heteroaryl, formyl radical, trifluoromethyl, trifluoromethoxy and (1-6C) alkyl;

The present invention preferably relates to and comprises the pharmaceutical composition of formula (I) derivative as active effective constituent, wherein:

R5 is an aryl;

R1 and R2 are hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl group or heteroaryl independently of one another, they itself are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, (1-6C) alkyl, (1-6C) alkoxyl group, CN, NO ₂, NH ₂, OH, COOH, COO alkyl, CONH ₂, formyl radical, trifluoromethyl or trifluoromethoxy;

The present invention also relates to the purposes of formula (I) Aminoindazole derivatives as medicine, wherein:

The invention particularly relates to the purposes of formula (I) Aminoindazole derivatives as medicine, wherein:

The present invention preferably relates to the purposes of formula (I) Aminoindazole derivatives as medicine, wherein:

R5 is an aryl;

Particularly, the present invention discloses following content:

Item 1: formula (I) compound:

Wherein:

Item 2: formula (I) compound:

Wherein:

Item 3: formula (I) compound:

Wherein:

R5 is an aryl;

Item 4: 1 compound is selected from:

6-chloro-7-fluoro-N-(3, the 3-dimethylbutyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3-phenyl propyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(cyclopropyl methyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(cyclopentyl-methyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(phenylethyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(cyclohexyl methyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-propyl group-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(4,4,4-trifluoro butyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(4-p-methoxy-phenyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(phenyl methyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(4-cyano-phenyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(3-p-methoxy-phenyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(4-fluorophenyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(3,3, the 3-trifluoro propyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(3-thienyl methyl)-1H-indazole-3-amine;

N-(1,1 '-xenyl-4-ylmethyl)-6-chloro-7-fluoro-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(5-methyl-2-furyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(1H-pyrroles-2-ylmethyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[(1H-imidazoles-2-yl) methyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[(1H-imidazol-4 yl) methyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(1H-pyrazole-3-yl methyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(3-thienyl methyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[2-(piperidino) ethyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[2-(4-morpholinyl) ethyl]-5-phenyl-1H-indazole-3-amine;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(2-propenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(phenyl methyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-Phenoxyphenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-p-methoxy-phenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-cyclohexyl urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-propyl group urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-chloro-phenyl-) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-fluorophenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-methyl-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-cyano group-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-cyclopropyl-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-hydroxyl-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-methoxyl group-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-trifluoromethyl-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-trifluoromethoxy-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-nitro-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-amino-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-dimethylamino-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-ethynyl-5-phenyl-1H-indazole-3-yl) urea;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-4-methyl-benzsulfamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl] Toluidrin;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-2-third sulphonamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-the 2-thiophenesulfonamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl] benzsulfamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-4-fluorobenzene sulphonamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl] the benzene Toluidrin;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-4-methylbenzene Toluidrin;

6-chloro-7-fluoro-N-(pentafluorophenyl group)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3, the 4-difluorophenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(2,3,5,6-tetrafluoro phenyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(2,4, the 6-trifluorophenyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(4-fluorophenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[3-(trifluoromethyl) phenyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[4-(trifluoromethyl) phenyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(4-nitrophenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3-nitrophenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3-p-methoxy-phenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(4-p-methoxy-phenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N, 5-phenylbenzene-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(1-pyridyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(2-pyridyl)-5-phenyl-1H-indazole-3-amine;

N-butyl-6-chloro-7-fluoro-5-phenyl-1H-indazole-3-amine;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-phenylurea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-3-methoxybenzenesulphoismide;

Item 5: the compound in the item 1 or 2 is selected from:

Its tautomer and pharmacologically acceptable salt thereof.

6: each the compound of item 1-5 that is used for preparing medicine.

7: pharmaceutical composition, this pharmaceutical composition contain among the 1-5 each compound in pharmaceutically acceptable medium.

8: 7 medicine, this medicine contain among at least a the 1-5 each compound, are used for the treatment of the disease that relates to the Protein tau phosphorylation.

Item 9: the medicine of item 6, this medicine contains among at least a the 1-5 each compound, is used for the treatment of neurodegenerative disease, apoplexy, cranium and trauma of spinal cord and peripheral neuropathy, obesity, metabolic disease, type ii diabetes, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, X syndrome, immune deficiency and cancer.

Item 10: the medicine of item 9, described neurodegenerative disease is Alzheimer, Parkinson's disease, os frontoparietale dementia, corticobasal degeneration or Pick's disease.

Item 11: the method for preparation 1 defined formula (I) compound, wherein in formula (I), R3 is (1-6C) alkyl, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, Heterocyclylalkyl, cycloalkyl or multi-ring alkyl, these groups are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, CN, NO ₂, NH ₂, OH, OR1, COOH, C (O) OR1 ,-O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S (O) R1, SO ₂R1, NHSO ₂R1, SO ₂NR1R2, C (S) NR1R2, NHC (S) R1 ,-O-SO ₂R1 ,-SO ₂-O-R1, aryl, heteroaryl, formyl radical, oxo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy or (1-6C) alkyl and R1, R2 are hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl group or heteroaryl independently of one another; they itself are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, (1-6C) alkyl, (1-6C) alkoxyl group, CN, NO ₂, NH ₂, OH, COOH, COO alkyl, CONH ₂, formyl radical, oxo, trifluoromethyl or trifluoromethoxy; Described method is included in the methylene dichloride, be that formula (I) derivative, R1CHO derivative and the sodium triacetoxy borohydride of H is prepared with R3 wherein, and resulting product does not transform or be converted into pharmacologically acceptable salt.

Item 12: the method for preparation 1 defined formula (I) compound, wherein in formula (I), R3 is that CONR1R2 or CSNR1R2 and R1 and R2 are hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl group or heteroaryl independently of one another, they itself are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, (1-6C) alkyl, (1-6C) alkoxyl group, CN, NO ₂, NH ₂, OH, COOH, COO alkyl, CONH ₂, formyl radical, oxo, trifluoromethyl or trifluoromethoxy; Described method is included in the tetrahydrofuran (THF), adopt OCNR1 and wherein R3 be that formula (I) derivative of H is prepared, and resulting product does not transform or is converted into pharmacologically acceptable salt.

Item 13: the method for preparation 1 defined formula (I) compound, wherein in formula (I), R3 is SO ₂R1 and R1 are hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl group or heteroaryl, and they itself are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, (1-6C) alkyl, (1-6C) alkoxyl group, CN, NO ₂, NH ₂, OH, COOH, COO alkyl, CONH ₂, formyl radical, oxo, trifluoromethyl or trifluoromethoxy; Described method is included in alkali and exists down, in methylene dichloride, uses SULPHURYL CHLORIDE R1SO ₂Cl and wherein R3 be that formula (I) derivative of H is prepared, and resulting compound does not transform or is converted into pharmacologically acceptable salt.

Item 14: midbody product, for:

6,7-two fluoro-1H-indazole-3-amine;

N-(6,7-two fluoro-1H-indazole-3-yls) butyramide:

N-[6,7-two fluoro-1-[[2-(three silyls) oxyethyl group] methyl]-1H-indazole-3-yl] butyramide;

N-[5-bromo-6,7-two fluoro-1-[[2-(three silyls) oxyethyl group] methyl]-1H-indazole-3-yl]-butyramide;

N-[6,7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-1H-indazole-3-yl] butyramide;

6,7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-1H-indazole-3-amine;

6,7-two fluoro-5-phenyl-1H-indazole-3-amine.Formula (I) derivative can be obtained by corresponding 3-aminoderivative (V), and wherein, 1-position nitrogen is unprotected or by group Pr protection.Pr be three silyl ethoxyl methyls, tosyl group, methylsulfonyl or benzyl or as T.W.Greene in " protecting group in the organic synthesis ", the group of pointing out among the J.Wiley-Interscience Publication (1999) that becomes known for protecting NH base in the aromatic heterocycle;

The amino 1H-indazole of formula (II) 3-can be according to R.F.Kaltenbach at Bioorg.Med.Chem.Lett., 9(15), method described in the 2259-62 (1999), by with 2-fluorine benzonitrile and hydrazine hydrate or hydrochloride at ethanol or just-obtained in back flow reaction 2-18 hour in the butanols.

Compound, wherein R5 and R6 are independently from each other following groups: halogen, CN, NO ₂, NH ₂, OH, COOH, C (O) OR8 ,-O-C (O) R8, NR8R9, NHC (O) R8, C (O) NR8R9, NHC (S) R8, C (S) NR8R9, SR8, S (O) R8, SO ₂R8, NHSO ₂R8, SO ₂NR8R9 ,-O-SO ₂R8 ,-SO ₂-O-R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxyl group, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, cycloalkyl, alkenyl, alkynyl group or adamantyl; These groups are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, CN, NO ₂, NH ₂, OH, OR10, COOH, C (O) OR10 ,-O-C (O) R10, NR10R11, NHC (O) R10, C (O) NR10R11, NHC (S) R10, C (S) NR10R11, SR10, S (O) R10, SO ₂R10, NHSO ₂R10, SO ₂NR10R11 ,-O-SO ₂R10 ,-SO ₂-O-R10, aryl, heteroaryl, formyl radical, oxo, trifluoromethyl, trifluoromethoxy or (1-6C) alkyl; Can by relate to the chemical reaction of palladium: Suzuki (A.Suzuki, Pure Appl.Chem., 63,419-22 (1991), Stille (J.Stille, Angew.Chem., Int.Ed., 25, 508-24 (1986)), Heck (R.F.Heck, Org.React., 27, 345-90 (1982)), Sonogashira, (K.Sonogashira, Synthesis, 777 (1977)), Buckwald (S.L.Buckwald, Acc.Chem.Re., 31, 805 (1998)), obtain by corresponding halide derivative.

For this reason, be necessary protective reaction functional group.Therefore, OH, SH, COOH and NH ₂Functional group must protect before carrying out coupling.Protecting group is according to well known by persons skilled in the art, and particularly T.W.Greene is in " protecting group in the organic synthesis ", and any method of describing among the J.Wiley-IntersciencePublication (1999) is introduced.Preferably with group such as tert-butoxycarbonyl or silicon derivative protection 1-position nitrogen.Preferably with tert-butyl dimethyl silanyl or three silyldisilanyls that can remove by fluoride anion or acetate, particularly with can be by the tetrabutylammonium (J.P.Whitten that in solvent such as tetrahydrofuran (THF) Huo diox, refluxes, J.Org.Chem., 51,1891 (1986); B.H.Lipshutz, Tetrahedron Lett., 4095 (1986)) or undertaken by in methyl alcohol or ethanol, reflux three silyl ethoxyl methyls of fracture of 2N hydrochloric acid.

The 1-position can be by initial compounds and three silyl ethoxymethyl chloride at room temperature with the derivative of three silyl ethoxyl methyls protections, in the presence of sodium hydride, reaction obtains (J.P.Whitten, J.Org.Chem. in solvent such as dimethyl formamide, 51,1891 (1986); M.P.Edwards, Tetrahedron, 42,3723 (1986)).

Similarly, the 1-NH nitrogen functional group of indazole will protect with group such as silyl derivative, benzyl, carbamate or tosyl group.For example, be coupled on the halogenated derivative in 6-position with palladium if desired, be necessary protection 1-as described below position nitrogen (X=Cl, Br or I):

Deprotection can be according to well known by persons skilled in the art and T.W.Greene in " protecting group in the organic synthesis ", and the method for describing among the J.Wiley-Interscience Publication (1999) is carried out.For example, if 1-position protecting group is three silyl ethoxyl methyls, it can be as described below by reacting deprotection with tetrabutylammonium so:

One in using the palladium chemical coupling in related R5 or the R6 base contains reactive functional groups, as hydroxyl, amine, mercaptan or carboxylic acid or when comprising heteroatoms usually, also is necessary carrying out protecting the latter before the coupling with palladium.Therefore, for example, phenol functional group will be introduced protection form (for example O-benzyl) by chlorinated derivatives, protect 1-position nitrogen as previously described:

Remove benzyl subsequently, for example undertaken by three silyl iodide reflow treatment in acetonitrile.Also can protect with three silyl ethoxyl methyls, described protecting group can be by tetrabutylammonium reflux in solvent such as tetrahydrofuran (THF) or diox (J.P.Whitten, J.Org.Chem., 51,1891 (1986); B.H.Lipshutz, Tetrahedron Lett., 4095 (1986)) or by the fracture that in methyl alcohol or ethanol, refluxes of 2N hydrochloric acid.

When R5 and R6 were aryl and halogen independently of one another, aryl functional group introduced by be coupled to the bromination position with palladium, and 1-and 3-position nitrogen are suitably protected.Preferably, Pr represent three silyl ethoxyl methyls and Pr ' expression just forming with nitrogen-butyl amide just-the butyl carbonyl.The acid amides deprotection steps refluxes in DMF and carries out in a week by in the presence of thanomin.This fracture also can be carried out (R J Griffin with tin protochloride in ethanol, J.Chem.Soc.Perkin I, 1992,1811-1819) or also can in methyl alcohol, carry out (Y.Furukawa with sodium methylate, Chem.Pharm.Bull., 1968,16,1076) or with any other alcoholate in corresponding alcohol, carry out.

When R5 and R6 were aryl and halogen independently of one another, aryl functional group introduced by be coupled to the bromination position with palladium, and 1-and 3-position nitrogen are suitably protected.Preferably, Pr represent three silyl ethoxyl methyls and Pr ' expression just forming with nitrogen-butyl amide just-the butyl carboxyl.For example electrophilic substitution is with nitronium tetrafluoroborate (NO ₂BF ₄) carry out.The coupling of 5-position utilizes the palladium chemistry to carry out (Suzuki, Heck or Sonogashira coupling).Introduce bromine or introduce aryl, heteroaryl, alkyl, alkenyl, alkynyl group or ethynyl by reduction, halogenation, the 7-bit function is turned to have required substituent function by palladium chemical coupling (Suzuki, Heck or Sonogashira coupling).The acid amides deprotection steps refluxes in DMF and carries out in a week by in the presence of thanomin.This fracture also can be carried out (R J Griffin with tin protochloride in ethanol, J.Chem.Soc.Perkin I, 1992,1811-1819) or also can in methyl alcohol, carry out (Y.Furukawa with sodium methylate, Chem.Pharm.Bull., 1968,16,1076) or with any other alcoholate in corresponding alcohol, carry out.3-position deprotection produces NH ₂Functional group, the radical reaction that it can be as described below and essential is introduced the 3-position with needed substituting group.

Formula (II) compound be preparation by the primary amine functional group of 3-Aminoindazole at all popular responses of this functional group, as: alkylation, acidylate, react reduction then, sulfonation with carbonyl derivative, be converted into urea or carbamate, arylation (Castro reaction or Buchwald reaction) wait in the initiator of various products of acquisition.

General formula (I) derivative, wherein R3 is H, when Pr is three silyl ethoxyl methyls, its reductive amination can be in " organic reaction ", 59 volumes, 1-714 (E.Baxter, A.Reitz) under the condition of describing in, in the presence of R1CHO type aldehyde, in methylene dichloride, utilize boron derivative such as sodium triacetoxy borohydride to carry out, or undertaken by other reductive agent that is generally used for reducing imines, form product, wherein R3 is (1-6C) alkyl, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, Heterocyclylalkyl, cycloalkyl or multi-ring alkyl, these groups are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, CN, NO ₂, NH ₂, OH, OR1, COOH, C (O) OR1 ,-O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S (O) R1, SO ₂R1, NHSO ₂R1, SO ₂NR1R2, C (S) NR1R2, NHC (S) R1 ,-O-SO ₂R1 ,-SO ₂-O-R1, aryl, heteroaryl, formyl radical, oxo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy or (1-6C) alkyl.

General formula (I) derivative, wherein R3 is H, with the condensation of OCNR1 type isocyanic ester especially can be in tetrahydrofuran (THF) and according to Comprehensive Organic Functional GroupTransformations, Vol.6 (Katritzky, Meth-Cohn, Rees 1995) in the embodiment that describes carry out, form product, wherein R3 is CONR1R2 or CSNR1R2, R1 and R2 are hydrogen independently of one another, (1-6C) alkyl, aryl, alkenyl, alkynyl group or heteroaryl, they itself are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, (1-6C) alkyl, (1-6C) alkoxyl group, CN, NO ₂, NH ₂, OH, COOH, COO alkyl, CONH ₂, formyl radical, oxo, trifluoromethyl or trifluoromethoxy.

General formula (I) derivative, wherein R3 is H, its sulfonation can exist down at alkali (tertiary amine particularly is as triethylamine, or aromatic amine, as pyridine), uses R1SO in conventional solvent such as methylene dichloride ₂C1 type SULPHURYL CHLORIDE is carried out, and forms product, and wherein R3 is SO ₂R1 and R1 are hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl group or heteroaryl, and they itself are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, (1-6C) alkyl, (1-6C) alkoxyl group, CN, NO ₂, NH ₂, OH, COOH, COO alkyl, CONH ₂, formyl radical, oxo, trifluoromethyl or trifluoromethoxy.

Separate type (I) compound and can for example carry out purifying by common known method by crystallization, chromatography or extraction.

Formula (I) compound can not transform or utilize inorganic or organic acid and by described acid at organic solvent, be converted into additive salt as the effect in alcohol, ketone, ether or the chlorinated solvent.These salt also constitute part of the present invention.

The example of pharmacologically acceptable salt can be mentioned following salt: benzene sulfonate, hydrobromate, hydrochloride, Citrate trianion, esilate, fumarate, gluconate, iodate, maleate, isethionate, mesylate, methylene radical two-β-chomene formate, nitrate, oxalate, embonate, phosphoric acid salt, salicylate, succinate, vitriol, tartrate, cariamyl and right-tosylate.

Formula (I) compound is kinase inhibitor and therefore is used for prevention and treatment neurodegenerative disease, Alzheimer, Parkinson's disease, os frontoparietale dementia, corticobasal degeneration, Pick's disease, apoplexy, cranium and trauma of spinal cord and peripheral neuropathy, obesity, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, X syndrome, immune deficiency and cancer.

Determine active by measuring to the inhibition of Protein tau phosphorylation in the section of adult rats pallium.

With 8-10 week macrandry OFA rat (Iffa-Credo) the preparation thickness of putting to death by detruncation is the pallium section of 300 μ m.They contain in the DMEM substratum of pyruvate salt and glucose 4.5g/l at 5ml, hatch under 37 ℃ 40 minutes.This substratum washed twice is used in this section subsequently, is divided in the microtubule (containing or do not contain packing 50 μ l in the substratum of test compound at 500 μ l) and hatches under 37 ℃ of stirrings.After two hours, by centrifugal termination test.Section is dissolved, ultrasonic and under 4 ℃, under 18300g centrifugal 15 minutes.(BCA Protein Assay Pierce) measures proteinic concentration by the commercial measuring method based on the Lowry method in the supernatant liquor.

In 4-12%Bis-tris setting type gel, separating also electromigration in the presence of the MOPS-SDS buffer reagent to the Nitrocellulose film at 10 minutes sample of 70 ℃ of following sex change in advance.Carry out with monoclonal antibody AD2 immune labeled, the Ser396/404 phosphorylation epitope of described monoclonal antibody specific recognition Protein tau.By add second kind of anti-mouse IgGs and with peroxidase link coupled antibody and chemoluminescence substrate development immune-reactive protein.(GeneGnome, ' GeneTools ' software Ozyme) come finally the radioactive automatic developing figure that is obtained to be carried out quantitatively so that measure IC to utilize Syngene ₅₀Value.

Formula (I) compound exhibits is very advantageously active, especially the IC of some compound ₅₀Value is less than 100 μ M.

The following example is illustrative rather than definitive thereof the present invention.

In the condition by the LC/MS assay products, the LC part is provided by Waters Alliance 2695 devices, and the mass spectrum part is provided by Waters-Micromass Platform II.

The preparation of midbody product:

6,7-two fluoro-1H-indazole-3-amine:

0.32cm ³The hydrazine monohydrate is added to 0.46cm ³2,3, the 10cm of 4-trifluoro benzonitrile ³In the ethanol solution.This medium was heated 17 hours down at about 75 ℃, add 10cm then ³Ethyl acetate, 5cm ³Tetrahydrofuran (THF) and 5cm ³Distilled water.The phase post precipitation separates organic phase and uses 10cm ³Distilled water wash is used 10cm then ³The saturated sodium-chloride water solution washing.The phase post precipitation separates organic phase, uses dried over mgso, filters and decompression (2kPa; 50 ℃) be concentrated into dried.Residue is by under the 50kPa Ar Pressure, at silicagel column (granularity 40-60 μ m; Diameter 1.5cm) goes up the chromatogram chromatography purification, with cyclohexane/ethyl acetate mixture (50/50 volume ratio) wash-out.Merge to contain and expect the cut of product, (2kPa then reduces pressure; 40 ℃) evaporation; Dry (90Pa; 40 ℃) after, 100mg 6 obtained, the white solid of 7-two fluoro-1H-indazole-3-amine, 183 ℃ of fusing points.

¹H NMR composes (300MHz, (CD ₃) ₂SO d6, δ represents with ppm): 5.57 (complicated peaks: 2H); 6.93 (mt:1H); (7.52 ddd, J=8.5-4.5 and 1Hz:1H); 12.01 (complicated peak: 1H).

N-(6,7-two fluoro-1H-indazole-3-yls) butyramide:

With 0.61cm ³It is above-mentioned 6 that butyryl chloride is added to 1g, the 15cm of 7-two fluoro-1H-indazole-3-amine ³In the pyridine solution, be cooled to about 3 ℃ after, mixture was at room temperature placed 76 hours.With reaction medium decompression (2kPa; 40 ℃) concentrate, residue is dissolved in 25cm ³Ethyl acetate and 25cm ³In the water.Organic phase 25cm ³Distilled water wash is used 25cm then ³The saturated sodium-chloride water solution washing.After dried over mgso, filter and decompression (2kPa; 40 ℃) concentrate, residue is by under the 50kPa Ar Pressure, at silicagel column (granularity 40-60 μ m; Diameter 3cm) goes up the chromatogram chromatography purification, with methylene chloride/methanol mixture (98/2 volume ratio) wash-out.Merge to contain and expect the cut of product, (2kPa then reduces pressure; 40 ℃) evaporation; Dry (90Pa; 40 ℃) after, the white solid of 596mg N-(6,7-two fluoro-1H-indazole-3-yls) butyramide, 191 ℃ of fusing points obtained.

¹H NMR composes (300MHz, (CD ₃) ₂SO d6, δ represents with ppm): 0.97 (t, J=7.5Hz:3H); 1.67 (mt:2H); 2.40 (t, J=7Hz:2H); 7.10 (mt:1H); (7.63 wide dd, J=9 and 4.5Hz:1H); 10.47 (the peak of wide complexity: 1H); 13.35 (the peak of wide complexity: 1H).

N-[6,7-two fluoro-1-[[2-(three silyls) oxyethyl group] methyl]-1H-indazole-3-yl] butyramide

180cm with 1.1g N-(6, the 7-two fluoro-1H-indazole-3-yls) butyramide of above-mentioned preparation ³Dimethyl formamide solution was added drop-wise to the 50cm of 1.65g sodium hydride 60% oily matter through 3 hours ³In the dimethyl formamide solution.Reaction medium is evaporated to dry doubling is dissolved in 250cm ³Ethyl acetate and 200cm ³In the water; The phase post precipitation divides organic phase, uses 150cm ³Dried over mgso is used in water washing, filters and decompression (2kPa; 50 ℃) be concentrated into dried.Crude product is by under the 50kPa Ar Pressure, at silicagel column (granularity 40-60 μ m; Diameter 6cm) goes up the chromatogram chromatography purification, with cyclohexane/ethyl acetate mixture (80/20 volume ratio) wash-out.Merge to contain and expect the cut of product and the (2kPa that reduces pressure; 50 ℃) evaporation, obtain 7.3g N-[6,7-two fluoro-1-[[2-(three silyls) oxyethyl group] methyl]-1H-indazole-3-yl] yellow oil of butyramide.

¹H NMR composes (300MHz, (CD ₃) ₂SO d6, δ represents with ppm) :-0.09 (s:9H); 0.82 (t, J=8Hz:2H); 0.96 (t, J=7.5Hz:3H); 1.67 (mt:2H); 2.41 (t, J=7Hz:2H); 3.56 (t, J=8Hz:2H); 5.66 (s:2H); (7.22 ddd, J=11-9 and 7Hz:1H); (7.69 wide dd, J=9 and 4.5Hz:1H); 10.60 (complicated peak: 1H).

Mass spectrum: M=369;

N-[5-bromo-6,7-two fluoro-1-[[2-(three silyls) oxyethyl group] methyl]-1H-indazole-3-yl]- Butyramide

With 0.87cm ³Pyridine is added to the above-mentioned N-[6 of 1g, 7-two fluoro-1-[[2-(three silyls) oxyethyl group] methyl]-1H-indazole-3-yl] 30cm of butyramide ³In the chloroformic solution, add 0.56cm then ³Bromine, mixture reflux and spend the night.With 50cm ³Methylene dichloride and 50cm ³10% sodium thiosulfate solution is added in this reaction medium.Stir after 10 minutes, by removing by filter insoluble substance with sinter funnel, organic phase 50cm ³Water and 50cm ³The saturated nacl aqueous solution washing.The phase post precipitation separates organic phase, with dried over mgso, filtration and decompression (2kPa; 45 ℃) be concentrated into dried.1.1g crude product is by under the 50kPa Ar Pressure, at silicagel column (granularity 40-60 μ m; Diameter 3cm) goes up the chromatogram chromatography purification, with cyclohexane/ethyl acetate mixture (90/10 volume ratio) wash-out.Merge to contain and expect the cut of product and the (2kPa that reduces pressure; 50 ℃) evaporation.Dry (90Pa; 45 ℃) after, obtain 230mg N-[5-bromo-6,7-two fluoro-1-[[2-(three silyls) oxyethyl group] methyl]-1H-indazole-3-yl] colorless oil of butyramide.

¹H NMR composes (300MHz, (CD ₃) ₂SO d6, δ represents with ppm) :-0.08 (s:9H); 0.82 (t, J=8Hz:2H); 0.96 (t, J=7.5Hz:3H); 1.67 (mt:2H); 2.42 (t, J=7Hz:2H); 3.55 (t, J=8Hz:2H); 5.66 (s:2H); (8.08 dd, J=6 and 2Hz:1H); 10.72 (complicated peak: 1H).

Mass spectrum: M=447;

N-[6,7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-1H-indazole-3- Base] butyramide

30cm with 469mg phenyl-boron dihydroxide, 760mg yellow soda ash ³The aqueous solution and 379mg tetrakis triphenylphosphine palladium are added to the N-[5-bromo-6 of the above-mentioned preparation of 1.15g, 7-two fluoro-1-[[2-(three silyls) oxyethyl group] methyl]-1H-indazole-3-yl] 150cm of butyramide ³In the dioxane solution, this mixture was refluxed 4 hours.Reaction medium 100cm ³Ethyl acetate and 75cm ³Water dilutes and filters by the sinter funnel of filling Celite.The phase post precipitation separates organic phase, with washing 75cm ³Water and 75cm ³Dried over mgso is used in the saturated nacl aqueous solution washing, filters and decompression (2kPa; 50 ℃) be concentrated into driedly, obtain the dark oil thing of 2g crude product.Crude product is by under the 50kPa Ar Pressure, at silicagel column (granularity 40-60 μ m; Diameter 3.5cm) goes up the chromatogram chromatography purification, with cyclohexane/ethyl acetate mixture (85/15 volume ratio) wash-out.Merge to contain and expect the cut of product, (2kPa reduces pressure; 50 ℃) evaporation and dry (90Pa, 45 ℃), obtain 1.1g N-[6,7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-1H-indazole-3-yl] yellow oil of butyramide.

¹H NMR composes (300MHz, (CD ₃) ₂SO d6, δ represents with ppm) :-0.05 (s:9H); 0.84 (t, J=8Hz:2H); 0.95 (t, J=7.5Hz:3H); 1.66 (mt:2H); 2.43 (t, J=7Hz:2H); 3.59 (t, J=8Hz:2H); 5.69 (s:2H); 7.40-7.65 (mt:5H); 7.82 (wide d, J=7Hz:1H); 10.64 (complicated peak: 1H).

Mass spectrum: M=445;

N-[6,7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-1H-indazole-3-amine

With 1.1cm ³Thanomin and 1.50g salt of wormwood successively are added to the above-mentioned N-[6 of 1.6g, 7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-1H-indazole-3-yl] 50cm of butyramide ³In the dimethyl formamide solution, mixture is refluxed a week.Reaction medium is evaporated to dry doubling and is dissolved in 150cm ³Ethyl acetate and 75cm ³In the water.The phase post precipitation separates organic phase and uses 75cm in succession ³* 2 water and 50cm ³The salt water washing.The organic phase dried over mgso is filtered and decompression (2kPa; 50 ℃) be concentrated into dried.Resulting crude product oily matter is by under the 50kPa Ar Pressure, at silicagel column (granularity 40-60 μ m; Diameter 4cm) goes up the chromatogram chromatography purification, with cyclohexane/ethyl acetate mixture (80/20 volume ratio) wash-out.Merge to contain and expect the cut of product and the (2kPa that reduces pressure; 50 ℃) evaporation.Dry (90Pa; 45 ℃) after, obtain 0.32g 6,7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-1H-indazole-3-amine.

6,7-two fluoro-5-phenyl-1H-indazole-3-amine:

1.1ml 2N HCl is added to 661mg 6,7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-the 15ml methanol solution of 1H-indazole-3-amine in.This is reflected at 140 ℃ of microwaves and carried out 3 minutes.Use saturated KH ₂PO ₄Solution hydrolysis and with behind the dichloromethane extraction, evaporating solvent, residue be chromatography (dichloromethane/ethyl acetate) on silica gel, obtains 314mg 6,7-two fluoro-5-phenyl-1H-indazole-3-amine.

Embodiment 1:Piperidines-1-formic acid (6,7-two fluoro-5-phenyl-1H-indazole-3-yl)-acid amides

Step 1

131 μ l pyridines and 154 μ l Vinyl chloroformates be added in succession 387.8mg (6,7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-the 8ml dichloromethane solution of 1H-indazole-3-amine compound in.After 75 minutes, reaction finishes.Extract after the hydrolysis and evaporation, obtain 840mg (6,7-two fluoro-5-phenyl-1H-indazole-3-yl) urethanum crude product.

Step 2

The 184mg piperidines is added in the 2.5ml phenylfluoroform of 161mg (6,7-two fluoro-5-phenyl-1H-indazole-3-yl) urethanum crude product, this is reflected under 200 ℃ of microwaves and carried out 20 minutes.Behind preparation LC/MS (acetonitrile/pH 9 damping fluids) purifying, obtain 80mg piperidines-1-formic acid (6,7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-1H-indazole-3-yl) acid amides.

Step 3

With 80mg piperidines-1-formic acid (6,7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-1H-indazole-3-yl) the 2.5ml methanol solution of acid amides is with 0.82ml 2N HCl reflow treatment 1 hour.Evaporation and by behind preparation LC/MS (acetonitrile/pH 9 damping fluids) purifying obtains 11mg piperidines-1-formic acid (6,7-two fluoro-5-phenyl-1H-indazole-3-yl) acid amides.

Mass spectrum: retention time 3.99; 357=[M+H] ⁺

¹H NMR spectrum (300MHz, (DMSO-d6, δ represent with ppm): 1.50 (m, 4H); 1.58 (m, 2H); 3.45 (m, 4H); 7.42 (m, 1H); 7.51 (m, 5H); 9.16 (s, 1H); 13.20 (bs, 1H)

Embodiment 2: tetramethyleneimine-1-formic acid (6,7-two fluoro-5-phenyl-1H-indazole-3-yl)-acid amides

Step 1

The 154mg tetramethyleneimine is added in the 2.5ml phenylfluoroform solution of 161mg (6,7-two fluoro-5-phenyl-1H-indazole-3-yl) urethanum, this is reflected under 200 ℃ of microwaves and carried out 20 minutes.Product is purifying on silicagel column, obtain 75mg tetramethyleneimine-1-formic acid (6,7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-1H-indazole-3-yl) acid amides.

Step 2

With 75mg tetramethyleneimine-1-formic acid (6,7-two fluoro-5-phenyl-1-[[2-(three silyls) oxyethyl groups] methyl]-1H-indazole-3-yl) the 3ml methanol solution of acid amides is with 0.82ml 2N HCl reflow treatment 1 hour.Evaporation and by behind preparation LC/MS (acetonitrile/pH 9 damping fluids) purifying obtains 36mg tetramethyleneimine-1-formic acid (6,7-two fluoro-5-phenyl-1H-indazole-3-yl) acid amides.

Mass spectrum: retention time 3.72 minutes; 343=[M+H] ⁺

¹H NMR spectrum (300MHz, (DMSO-d6, δ represent with ppm): 1.86 (m, 4H); 3.40 (m, 4H); 7.42 (m, 1H); 7.45-7.54 (m, 4H); 7.63 (bd, J=7Hz, 1H); 8.84 (s, 1H); 13.20 (bs, 1H);

Embodiment 3: carry out according to embodiment 2, begin, obtain 1-(6,7-two fluoro-5-phenyl-1H-indazole-3-yl)-3-[3-(4-methylpiperazine-1-yl) propyl group with 3-(4-methylpiperazine-1-yl) propyl group amine] urea.

¹H NMR spectrum (300MHz, (DMSO-d6, δ represent with ppm): 1.92 (m, 2H); 2.82 (s, 3H); 3.01-3.75 (m, part is sheltered, 12H); 7.43 (m, 1H); From 7.47-7.56 (m, 4H); 7.71 (t, J=7Hz, 1H); 8.05 (dd, J=1.5-7Hz, 1H); 9.61 (s, 1H);

Mass spectrum: retention time 2.57 minutes; 429=[M+H] ⁺

Pharmaceutical composition of the present invention comprise pure state or with any other can be formula (I) compound of composition forms of pharmaceutically acceptable product combination of inert or physiologically active or the salt of described compound.Medicine of the present invention can be by oral, parenteral route, rectum or topical.

The solids composition of oral administration can use tablet, pill, pulvis (hard gelatin capsule, cachet) or granule.In these compositions, effective constituent of the present invention under argon gas with one or more inert diluents, mix as starch, Mierocrystalline cellulose, sucrose, lactose or silicon-dioxide.These compositions can also comprise the material except that thinner, and one or more lubricants for example are as Magnesium Stearate or talcum powder, tinting material, Drug coating (drageeing) or glaze.

The liquid composition of oral administration can use and comprise inert diluent, as pharmaceutically acceptable solution, suspension, emulsion, syrup and the elixir of water, ethanol, glycerine, vegetables oil or whiteruss.These compositions can comprise the material except that thinner, for example wetting agent, sweeting agent, thickening material, correctives or stablizer.

The aseptic composite of parenteral administration preferably can be solution, suspension or the emulsion of water or non-water form.Solvent or carrier can make water, propylene glycol, polyoxyethylene glycol, vegetables oil, particularly sweet oil, injectable organic ester, for example ethyl oleate or other suitable organic solvent.These compositions also can comprise adjuvant, particularly wetting agent, isotonic regulator, emulsion, dispersion agent and stablizer.Can be by several modes, for example by sterile filtration, in composition, incorporate sterilant, irradiation or heat sterilization into and sterilize.They also can be prepared into the sterilization solids composition form that can be dissolved in use in sterilization water or any other sterile medium.

The composition of rectal administration is suppository or rectum capsule, and they contain vehicle except that active result, as theobroma oil, semi-synthetic glyceryl ester or polyoxyethylene glycol.

Topical drug delivery composition can be, for example creme, lotion, eye drops, collutory, nasal drop or aerosol.

To be formula (I) Aminoindazole compound and pharmacologically acceptable salt thereof and they be used to prevent and treat the pharmaceutical composition of the disease that abnormal kinase causes in the preparation expection to theme of the present invention, for example, described disease relates to neurodegenerative disease, Alzheimer, Parkinson's disease, the os frontoparietale dementia, corticobasal degeneration, Pick's disease, apoplexy, cranium and trauma of spinal cord and peripheral neuropathy, obesity, metabolic disease, type ii diabetes, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, X syndrome, immune deficiency and cancer.

Abnormal kinase can mention, for example PI3K, AkT or GSK3 'beta ' activity are unusual, CDKs is active unusual etc.

In the mankind's treatment, The compounds of this invention be used in particular for treatment and/prevention neurodegenerative disease, Alzheimer, Parkinson's disease, os frontoparietale dementia, corticobasal degeneration, Pick's disease, apoplexy, cranium and trauma of spinal cord and peripheral neuropathy, obesity, metabolic disease, type ii diabetes, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, X syndrome, immune deficiency and cancer.

Dosage depends on expected results, treatment time length and employed route of administration; Grownup's oral dosage every day is usually at 5mg-1000mg, and unitary dose is the 1mg-250mg active substance.

Usually, the doctor will be that specific factor is determined appropriate dosage for the treatment experimenter according to age, body weight and all.

The following example is used to illustrate composition of the present invention.

Embodiment A

The hard gelatin capsule that contains 50mg active ingredient and following component according to the usual method preparation:

-Shi (I) compound ... ... ... ... ... ... ... ... ... ... ... 50mg

-Mierocrystalline cellulose ... ... ... ... ... ... ... ... ... ... ... ..18mg

-lactose ... ... ... ... ... ... ... ... ... ... ... ... .55mg

-silica gel ... ... ... ... ... ... ... ... ... ... ... ... .1mg

-sodium starch glycolate ... ... ... ... ... ... ... ... ... ... ..10mg

-talcum powder ... ... ... ... ... ... ... ... ... ... ... ..10mg

-Magnesium Stearate ... ... ... ... ... ... ... ... ... ... ... 1mg

Embodiment B

The tablet that contains 50mg active ingredient and following component according to the usual method preparation:

-Shi (I) compound ... ... ... ... ... ... ... ... ... ... ... 50mg

-lactose ... ... ... ... ... ... ... ... ... ... ... ..104mg

-Mierocrystalline cellulose ... ... ... ... ... ... ... ... ... ... ... 40mg

-polyvidone ... ... ... ... ... ... ... ... ... ... ... 10mg

-sodium starch glycolate ... ... ... ... ... ... ... ... ... ... 22mg

-talcum powder ... ... ... ... ... ... ... ... ... ... ... 10mg

-Magnesium Stearate ... ... ... ... ... ... ... ... ... ... .2mg

-silica gel ... ... ... ... ... ... ... ... ... ... ... ..2mg

The mixture of-Walocel MT 20.000PV, glycerine and titanium oxide (72/3.5/24.5) is an amount of

Every coating tablet 245mg

Embodiment C

Preparation comprises the Injectable solution of 10mg active result and following component:

-Shi (I) compound ... ... ... ... ... ... ... ... ... ... .10mg

-phenylformic acid ... ... ... ... ... ... ... ... ... ... ... 80mg

-phenylcarbinol ... ... ... ... ... ... ... ... ... ... ... 0.06ml

-Sodium Benzoate ... ... ... ... ... ... ... ... ... ... .80mg

-95% ethanol ... ... ... ... ... ... ... ... ... ... .0.4ml

-sodium hydroxide ... ... ... ... ... ... ... ... ... ... .24mg

-propylene glycol ... ... ... ... ... ... ... ... ... ... ... 1.6ml

-water ... ... ... ... ... ... ... ... ... ... .... in right amount to 4ml

The present invention also relates to prevent and treat the method for the disease that relates to the Protein tau phosphorylation by giving construction (I) compound and pharmacologically acceptable salt thereof.

Claims

1. formula (I) compound:

Wherein:

R3 be (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, with (1-1OC) Cycloalkylfused aryl or heteroaryl, heterocycle, Heterocyclylalkyl, cycloalkyl, adamantyl, multi-ring alkyl, alkenyl, alkynyl group, CONR1R2, CSNR1R2, COOR1, SO ₂R1, C (=NH) R1 or C (=NH) NR1 base; These groups are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, CN, NO ₂, NH ₂, OH, OR1, COOH, C (O) OR1 ,-O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S (O) R1, SO ₂R1, NHSO ₂R1, SO ₂NR1R2, C (S) NR1R2, NHC (S) R1 ,-O-SO ₂R1 ,-SO ₂-O-R1, aryl, heteroaryl, heterocycle, formyl radical, trifluoromethyl, trifluoromethylthio, trifluoromethoxy or (1-6C) alkyl;

2. formula (I) compound:

Wherein:

3. formula (I) compound:

Wherein:

R5 is an aryl;

4. claim 1 compound is selected from:

6-chloro-7-fluoro-N-(3, the 3-dimethylbutyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3-phenyl propyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(cyclopropyl methyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(cyclopentyl-methyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(phenylethyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(cyclohexyl methyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-propyl group-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(4,4,4-trifluoro butyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(4-p-methoxy-phenyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(phenyl methyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(4-cyano-phenyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(3-p-methoxy-phenyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(4-fluorophenyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(3,3, the 3-trifluoro propyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(3-thienyl methyl)-1H-indazole-3-amine;

N-(1,1 '-xenyl-4-ylmethyl)-6-chloro-7-fluoro-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[(5-methyl-2-furyl) methyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(1H-pyrroles-2-ylmethyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[(1H-imidazoles-2-yl) methyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[(1H-imidazol-4 yl) methyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(1H-pyrazole-3-yl methyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(3-thienyl methyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-[2-(piperidino) ethyl]-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[2-(4-morpholinyl) ethyl]-5-phenyl-1H-indazole-3-amine;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(2-propenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(phenyl methyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-Phenoxyphenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-p-methoxy-phenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-cyclohexyl urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-propyl group urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-chloro-phenyl-) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-(4-fluorophenyl) urea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-methyl-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-cyano group-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-cyclopropyl-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-hydroxyl-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-methoxyl group-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-trifluoromethyl-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-trifluoromethoxy-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-nitro-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-amino-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-dimethylamino-5-phenyl-1H-indazole-3-yl) urea;

N-(6-chloro-7-ethynyl-5-phenyl-1H-indazole-3-yl) urea;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-4-methyl-benzsulfamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl] Toluidrin;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-2-third sulphonamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-the 2-thiophenesulfonamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl] benzsulfamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-4-fluorobenzene sulphonamide;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl] the benzene Toluidrin;

N-[6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl]-4-methylbenzene Toluidrin;

6-chloro-7-fluoro-N-(pentafluorophenyl group)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3, the 4-difluorophenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(2,3,5,6-tetrafluoro phenyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-5-phenyl-N-(2,4, the 6-trifluorophenyl)-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(4-fluorophenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[3-(trifluoromethyl) phenyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-[4-(trifluoromethyl) phenyl]-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(4-nitrophenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3-nitrophenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(3-p-methoxy-phenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(4-p-methoxy-phenyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N, 5-phenylbenzene-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(1-pyridyl)-5-phenyl-1H-indazole-3-amine;

6-chloro-7-fluoro-N-(2-pyridyl)-5-phenyl-1H-indazole-3-amine;

N-butyl-6-chloro-7-fluoro-5-phenyl-1H-indazole-3-amine;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-N '-phenylurea;

N-(6-chloro-7-fluoro-5-phenyl-1H-indazole-3-yl)-3-methoxybenzenesulphoismide;

5. the compound in the claim 1 or 2 is selected from:

Its tautomer and pharmacologically acceptable salt thereof.

6. be used for preparing each the compound of claim 1-5 of medicine.

7. pharmaceutical composition, this pharmaceutical composition contain among the claim 1-5 each compound in pharmaceutically acceptable medium.

8. the medicine of claim 7, this medicine contain among at least a claim 1-5 each compound, are used for the treatment of the disease that relates to the Protein tau phosphorylation.

9. the medicine of claim 6, this medicine contains among at least a claim 1-5 each compound, is used for the treatment of neurodegenerative disease, apoplexy, cranium and trauma of spinal cord and peripheral neuropathy, obesity, metabolic disease, type ii diabetes, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, X syndrome, immune deficiency and cancer.

10. the medicine of claim 9, described neurodegenerative disease is Alzheimer, Parkinson's disease, os frontoparietale dementia, corticobasal degeneration or Pick's disease.

11. prepare the method for the defined formula of claim 1 (I) compound, wherein in formula (I), R3 is (1-6C) alkyl, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, Heterocyclylalkyl, cycloalkyl or multi-ring alkyl, these groups are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, CN, NO ₂, NH ₂, OH, OR1, COOH, C (O) OR1 ,-O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S (O) R1, SO ₂R1, NHSO ₂R1, SO ₂NR1R2, C (S) NR1R2, NHC (S) R1 ,-O-SO ₂R1 ,-SO ₂-O-R1, aryl, heteroaryl, formyl radical, oxo, trifluoromethyl, trifluoromethylthio, trifluoromethoxy or (1-6C) alkyl and R1, R2 are hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl group or heteroaryl independently of one another; they itself are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, (1-6C) alkyl, (1-6C) alkoxyl group, CN, NO ₂, NH ₂, OH, COOH, COO alkyl, CONH ₂, formyl radical, oxo, trifluoromethyl or trifluoromethoxy; Described method is included in the methylene dichloride, be that formula (I) derivative, R1CHO derivative and the sodium triacetoxy borohydride of H is prepared with R3 wherein, and resulting product does not transform or be converted into pharmacologically acceptable salt.

12. prepare the method for the defined formula of claim 1 (I) compound, wherein in formula (I), R3 is that CONR1R2 or CSNR1R2 and R1 and R2 are hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl group or heteroaryl independently of one another, they itself are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, (1-6C) alkyl, (1-6C) alkoxyl group, CN, NO ₂, NH ₂, OH, COOH, COO alkyl, CONH ₂, formyl radical, oxo, trifluoromethyl or trifluoromethoxy; Described method is included in the tetrahydrofuran (THF), adopt OCNR1 and wherein R3 be that formula (I) derivative of H is prepared, and resulting product does not transform or is converted into pharmacologically acceptable salt.

13. prepare the method for the defined formula of claim 1 (I) compound, wherein in formula (I), R3 is SO ₂R1 and R1 are hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl group or heteroaryl, and they itself are unsubstituted or by one or more substituting groups replacements, described substituting group is selected from halogen, (1-6C) alkyl, (1-6C) alkoxyl group, CN, NO ₂, NH ₂, OH, COOH, COO alkyl, CONH ₂, formyl radical, oxo, trifluoromethyl or trifluoromethoxy; Described method is included in alkali and exists down, in methylene dichloride, uses SULPHURYL CHLORIDE R1SO ₂Cl and wherein R3 be that formula (I) derivative of H is prepared, and resulting compound does not transform or is converted into pharmacologically acceptable salt.

14. midbody product, for:

6,7-two fluoro-1H-indazole-3-amine;

N-(6,7-two fluoro-1H-indazole-3-yls) butyramide:

6,7-two fluoro-5-phenyl-1H-indazole-3-amine.